New data from the Italian National Register of Congenital Coagulopathies, 2016 Annual Survey.

BACKGROUND: In Italy, the National Register of Congenital Coagulopathies (NRCC) collects epidemiological and therapeutic data from patients affected by haemophilia A (HA), haemophilia B (HB), von Willebrand's disease (vWD) and other rare coagulation disorders. Here we present data from the 2016 annual survey. MATERIALS AND METHODS: Data are provided by the Italian Haemophilia Centres, on a voluntary basis. Information flows from every Centre to a web-based platform of the Italian Association of Haemophilia Centres, shared with the Italian National Institute of Health, in accordance with current privacy laws. Patients are classified by diagnosis, disease severity, age, gender and treatment-related complications. RESULTS: In 2016, the total number of patients with congenital coagulopathies in the NRCC was 10,360: 39.8% of these patients had HA, 31.5% had vWD, 8.5% had HB, and 20.2% had less common factor deficiencies. The overall prevalence of HA and HB was 13.9/100,000 males and 3.0/100,000 males, respectively. The overall prevalence of vWD was 5.4/100,000 inhabitants. During 2016, 126 patients had current alloantibodies to factor VIII (FVIII) or factor IX (FIX) and were under treatment with bypassing agents and/or immune tolerance induction. Overall, 388 patients with a history of alloantibodies were recorded in the NRCC of whom 337 with severe HA and 12 with severe HB. Coagulation factor use, evaluated from treatment plans, was approximately 451,000,000 IU of FVIII for HA patients (7.5 IU/inhabitant), and approximately 53,000,000 IU of FIX for HB patients (0.9 IU/inhabitant). DISCUSSION: The prevalences of HA and HB fall within the ranges reported in more developed countries; the consumption of FVIII and FIX was in line with that of other European countries (France, United Kingdom) and Canada. The NRCC, with its bleeding disorder dataset, is a helpful tool for shaping public health policies, as well as planning clinical and epidemiological research projects.

Rare clotting factor deficiency among Sudanese children.

: Rare clotting factor (F) deficiency is a deficiency of one or more of coagulation factors other than FVIII, FIX and vonWillebrand (FI, FII, FV, FV + FVIII, FVII, FIX, FX, FXI and FXIII) that cause bleeding disorders and are inherited as autosomal recessive. Descriptive study was conducted in Hemophilia Centre, Khartoum, Sudan. The medical files of pediatric patients presented to the center were reviewed retrospectively. Forty-seven patients (male : female ratio = 1.2 : 1) were included. The majority (93.6%) have parental history of consanguinity and around one third (31.9%) have family history of bleeding disorder. FV deficiency was the most common deficient factor (36.2%) followed by FI deficiency (23.4%) and FX111 deficiency (21.3%). Bruising (46.8%) and epistaxis (25.5%) were the most common presenting complains. FV deficiency mainly presented with cutaneous ecchymosis (47.1%). FI deficiency presented with umbilical bleeding (45.5%) and FXIII presented with cutaneous ecchymosis (50%). Rare clotting factor deficiency is an existing disease in Sudan with the male : female ratio was 1.2 : 1. FV deficiency, FI deficiency, FXIII deficiency were the common deficiency encountered.

FranceCoag: a 22-year prospective follow-up of the national French cohort of patients with inherited bleeding disorders.

FranceCoag is an ongoing open prospective multicentre cohort project aimed at improving epidemiological knowledge about inherited bleeding disorders in France. The main objective of this article was to evaluate the project's progress as of the 30th December 2016. Between 1994 and this date, of the 10,047 patients included in the study, 384 (3.8%) were reported by clinicians to have died and 159 (1.6%) to be lost to follow-up. Among the remaining 9504 patients still being followed up, 5748 (60.5%) had haemophilia A, 1300 (13.7%) haemophilia B, 1980 (20.8%) von Willebrand Disease while 476 (5.0%) had another clotting factor deficiency (Factor I, II, V, combined V and VIII, VII, X, XI and XIII). The median age of the population was 32 years (Inter-quartile range (IQR) 18-50 years) at data extraction on December 30th, 2016. The subgroup of children (i.e., < 18 years old) with severe haemophilia and comprehensive information available since the first exposure to treatment was identified as the PUPs (Previously Untreated Patients) cohort. Data for the 643 children included in the PUPs' cohort had been collected since their birth. Follow-up data were collected by the clinicians in haemophilia treatment centres (HTC) every 12.9 months on median (IQR 11.4-21.3). In the PUPS cohort, data were updated every 6.2 months on median (IQR 3.7-11.7). A unique patient number assigned at study inclusion was kept at individual HTC by participating clinicians. The data collected included demographic, clinical, therapeutic and biological items on standard electronic forms. As of December 30th 2016, a plasma and serum samples was available for 2581 patients (27.1%).

Plasma contact factors as therapeutic targets.

Direct oral anticoagulants (DOACs) are small molecule inhibitors of the coagulation proteases thrombin and factor Xa that demonstrate comparable efficacy to warfarin for several common indications, while causing less serious bleeding. However, because their targets are required for the normal host-response to bleeding (hemostasis), DOACs are associated with therapy-induced bleeding that limits their use in certain patient populations and clinical situations. The plasma contact factors (factor XII, factor XI, and prekallikrein) initiate blood coagulation in the activated partial thromboplastin time assay. While serving limited roles in hemostasis, pre-clinical and epidemiologic data indicate that these proteins contribute to pathologic coagulation. It is anticipated that drugs targeting the contact factors will reduce risk of thrombosis with minimal impact on hemostasis. Here, we discuss the biochemistry of contact activation, the contributions of contact factors in thrombosis, and novel antithrombotic agents targeting contact factors that are undergoing pre-clinical and early clinical testing.

Autosomal recessive inherited bleeding disorders in Pakistan: a cross-sectional study from selected regions.

BACKGROUND: Autosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16. RESULTS: Of the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard-Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each. CONCLUSION: vWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.

How do we encounter rare factor deficiencies in children? Single-centre results from Turkey.

BACKGROUND: Rare factor deficiencies (RFDs) are autosomal recessively inherited coagulation factor deficiencies encountered at a frequency of between one in 500, 000 and one in two million. MATERIALS AND METHODS: One hundred and ninety-two patients, diagnosed as having RFD, followed and treated in our clinic between 1990 and 2013 were retrospectively evaluated in this study. RESULTS: From the 192 patients, 142 had FVII, 15 had FX, 14 had FXI, 10 had fibrinogen, six had FV, two had FXIII, two had FV + FVIII and one had FII deficiency. One hundred and thirty of the cases were boys and 62 were girls. The age range was 2 weeks to 24 years and the ages at the admission were between 2 weeks and 16 years. The rate of consanguinity was 49.4%. Eighty-eight of our patients were asymptomatic (45.8%) and 104 were symptomatic (54.2%). Asymptomatic patients were diagnosed by family histories (39.8%), preoperative laboratory studies (54.6%) and operational bleeding (5.6%). Sixty-eight of our symptomatic patients displayed grade II (65.4%) and 36 displayed grade III bleeding symptoms (34.6%). First bleeding regions were skin (33%), nose (28%), central nervous system (CNS) (15.5%), oral cavity (10.5%), soft tissue (6%), joint (3%), urinary system (2%) and gastrointestinal system (GIS) (2%), respectively. The bleeding prevalence rates of our symptomatic patients are listed as epistaxis 62.5%, skin bleedings 53%, oral cavity bleeding 28.8%, haematomas 18.3%, CNS bleedings 17.3%, haemarthrosis 14.4%, GIS bleedings 3.8%, menorrhagia 2.9%, haematuria 1.9%, bleeding because of operations 1.9% and iliopsoas bleedings 1.9%. CNS bleedings (41%) take the first place among the serious bleedings of our cases, followed by haemarthrosis (36.4%), GIS bleedings (18.1%) and iliopsoas bleedings (4.5%). Prophylaxy was applied to nine patients (five patients with FVII, two patients with fibrinogen and one each with FV and FX deficiency). CONCLUSIONS: The characteristics of clinical presentations, first bleeding attacks, bleeding prevalence and severe bleedings as well as prophylactic approaches are discussed in this article.

Rare coagulation factor deficiencies: a countrywide screening data from India.

As compared to haemophilia, although the clinical features and the management strategies for rare coagulation factor deficiencies are discussed, little is known about them. This study was undertaken to assess the distribution, clinical presentation and treatment of patients with rare coagulation factor deficiency disorders in a cross-sectional population of India. Blood samples and other clinical details from patients suspected of rare coagulation factor deficiencies were collected by the Haemophilia Treatment Centers across India and were diagnosed at National Institute of Immunohaematology, Mumbai. A total of 321 cases of rare clotting factor deficiencies were diagnosed, of which 88% were severe, 10% moderate and 2% mild. Commonest deficiency encountered was factor XIII (FXIII) (30%) followed by FX (15.6%), FVII (15%), fibrinogen (12.1%), FXI (9%), combined V and VIII deficiency (5.6%) and congenital multiple vitamin K-dependent coagulation factor deficiency (MCFD, 2.1%). Major representation of these deficiencies was from Southern and Western India (82%). Mucocutaneous bleeding was the commonest clinical presentation (59%); intracranial (IC) haemorrhage was seen in 18% of the patients; menorrhagia was an important clinical pointer in women in the reproductive age group (78%); 8% of the severe cases had no history of bleeding and 73% of the FXIII deficiency cases had umbilical stump bleeding. The major therapeutic products used was fresh frozen plasma (64%), cryoprecipitate (15%), whole blood (15%), antifibrinolytics (5%) and recombinant FVIIa (1%). A distinct pattern in the distribution of rare clotting factor deficiencies was observed which was based on multiple factors that include ethnicity and the available diagnostic facilities in different regions of this vast country.

Prevalence of hemostatic disorders in adolescents with abnormal uterine bleeding.

STUDY OBJECTIVE: To evaluate the incidence of hemostatic disorders in a population of adolescents with various patterns of abnormal uterine bleeding (AUB). DESIGN: Retrospective observational study. SETTING: University hospital. PARTICIPANTS: One hundred thirteen adolescents with AUB; mean age at menarche and mean age at the onset of symptoms 12 ± 1.2 years and 13.5 ± 2.8 years, respectively. MAIN OUTCOME MEASURES: Data on menstrual history, bleeding symptoms, co-existing medical conditions, and medical therapies were assessed. All patients were screened for hemostatic disorders with laboratory testing. The incidence of the disorders was calculated. Subjects were further divided in 2 groups based on whether the AUB started in the first 2 years from menarche (group 1) or later (group 2). A statistical analysis was performed using a chi-square test to compare incidence of hemostatic disorders between the groups. RESULTS: One hundred thirteen adolescents with AUB were identified. Overall, 54 (47.8%) patients had some underlying hemostatic disorder, of which a platelet dysfunction was the most common (17.7%). Von Willebrand disease was detected in 13.3% of cases and a deficiency of a coagulation factor in 12.4%. In 7.1% of patients an isolated increase of bleeding time was observed. When divided in 2 groups, 44.2% of patients in group 1 and 59.2% in group 2 had a coagulation disorders, with no statistically significant difference between the 2 groups (P = .17). CONCLUSION: AUB in adolescents is frequently associated with an underlying disorder of hemostasis, most commonly a platelet function disorder. The results highlight the importance of screening for coagulation disorders in adolescents with AUB, independently from the gynecologic age at onset.

[Rare bleeding disorders and invasive procedures]. / Déficits rares de la coagulation et gestes invasifs.

Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V+VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.

Clotting factor deficiency in early trauma-associated coagulopathy.

BACKGROUND: Coagulopathic bleeding is a leading cause of in-hospital death after injury. A recently proposed transfusion strategy calls for early and aggressive frozen plasma transfusion to bleeding trauma patients, thus addressing trauma-associated coagulopathy (TAC) by transfusing clotting factors (CFs). This strategy may dramatically improve survival of bleeding trauma patients. However, other studies suggest that early TAC occurs by protein C activation and is independent of CF deficiency. This study investigated whether CF deficiency is associated with early TAC. METHODS: This is a prospective observational cohort study of severely traumatized patients (Injury Severity Score ≥ 16) admitted shortly after injury, receiving minimal fluids and no prehospital blood. Blood was assayed for CF levels, thromboelastography, and routine coagulation tests. Critical CF deficiency was defined as ≤ 30% activity of any CF. RESULTS: Of 110 patients, 22 (20%) had critical CF deficiency: critically low factor V level was evident in all these patients. International normalized ratio, activated prothrombin time, and, thromboelastography were abnormal in 32%, 36%, and 35%, respectively, of patients with any critically low CF. Patients with critical CF deficiency suffered more severe injuries, were more acidotic, received more blood transfusions, and showed a trend toward higher mortality (32% vs. 18%, p = 0.23). Computational modeling showed coagulopathic patients had pronounced delays and quantitative deficits in generating thrombin. CONCLUSIONS: Twenty percent of all severely injured patients had critical CF deficiency on admission, particularly of factor V. The observed factor V deficit aligns with current understanding of the mechanisms underlying early TAC. Critical deficiency of factor V impairs thrombin generation and profoundly affects hemostasis.

Comparative incidence of thrombosis in reported cases of deficiencies of factors of the contact phase of blood coagulation.

Thrombotic manifestations occurring in patients with coagulation defects have drawn considerable attention during the last decade. It concerned mainly patients with hemophilia, vW disease or FVII deficiency. Occasional reports involved also the deficiencies of the contact phase of blood coagulation, mainly FXII deficiency. The purpose of the present study was to evaluate the comparative incidence of thrombosis in all reported patients with FXII, Prekallikrein and Kininogens deficiencies. Out of the reported 341 cases with these conditions that could be tracked there were 43 cases with thrombosis. More specifically, there were 32 patients with FXII deficiency who also had a thrombotic event (16 arterial and 16 venous). As far as Prekallikrein deficiency is concerned, there were nine cases with thrombosis (five arterial and four venous). Finally, two patients with Total or High molecular weight Kininogen deficiencies had also a thrombotic manifestation (one arterial and one venous). The thrombotic manifestations were M.I. 11 cases; ischemic stroke 9 cases; peripheral arteries 3 cases; deep vein thrombosis with or without pulmonary embolism 17 cases; thrombosis in other veins 3 cases. Congenital or acquired associated prothrombotic risk factors were present in 33 out of 36 cases. In three cases the existence of associated risk factors was excluded whereas in the remaining seven patients no mention is made in this regard. This study clearly indicates that the severe in vitro coagulation defect seen in these conditions does not protect from thrombosis.

Superficial venous thrombosis: role of inherited deficiency of natural anticoagulants in extension to deep veins.

AIM: Superficial venous thrombosis (SVT) has been considered for a long time a limited clinical condition of low importance, but this approach has changed in recent years, when several studies demonstrated that extension to deep veins occurs in 7.3 to 44% of patients, with high prevalence of pulmonary embolism. The aim of this study was to evaluate the prevalence of inherited deficiency of natural coagulation inhibitors in patients suffering from SVT in both normal and varicose veins, and to understand their role in extension to deep veins. METHODS: The study included 83 patients with SVT, without clinically obvious risk factors. Ultrasound examination was performed, and deficiencies of Protein C, Protein S and Antithrombin (AT) were investigated. RESULTS: In the patients where SVT occurred in normal veins, coagulation inhibitor deficiencies were 6.45% in the absence of extension and 62.5% in patients with extension to deep veins. In the patients with varicose vein SVT, the presence of these factors was less evident, but their prevalence was considerably higher in those with extension to deep veins (36.3%) than in non-extension (6.06%). CONCLUSIONS: Present data confirm the role of inherited thrombophilic states related to inhibitor deficiency, considering them as risk factors for SVT in normal veins. Furthermore, an association has been found between their presence and the progression of SVT to deep veins.

Coagulation disorders and inhibitors of coagulation in children from Mansoura, Egypt.

Disorders of coagulation in children often prove challenging to the medical care team. The aims of this study were to assess the spectrum and prevalence of coagulation disorders among children attending Mansoura University Children Hospital (MUCH), Mansoura, Egypt. A total of 105 pediatric patients were referred to MUCH. They were divided into two groups: congenital coagulation disorders (75 cases, age 45.36 +/- 48.59 months), and acquired coagulation disorders (30 cases, age 56.13 +/- 61.61 months). All patients were subjected to thorough history taking including the nature of bleeding, family, past history, mode of inheritance, and detailed physical findings. Hemostatic tests included: platelet count, bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). Specific tests in the congenital group include assay of coagulation factors according to each disorder, Von Willebrand factor assay, ristocetin aggregation test, APTT mixing study for detection of inhibitors in complicated hemophilia cases, F VIII C to VWAg ratio with cut off 0.7 for detection of carriers in some hemophilia A families. Congenital disorders constituted 71.4% of the studied cases vs. 28.6% for acquired disorders. Hemophilia A (42.85%), hemophilia B (14.28%) and liver diseases (14.28%) represented the majority of the studied cases. Mild and moderate cases of hemophilia A and B are more frequent than severe cases in both types. Male sex is more frequent than female in the congenital group (94.7 vs. 5.3%, P < 0.001). Direct correlation existed between factor level assay and severity of hemophilia (r = 0.73, P = 0.006). Three mothers and one sister were identified as carrier out of four families. Anti-clotting factors inhibitor was detected in 18.2% of patients with hemophilia A and in 9.1% with hemophilia B. In conclusion, our study found that hemophilias are the most prevalent congenital coagulation disorders among children. Attention must be given for detection of hemophilia carriers and inhibitors of clotting factors.

High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls.

BACKGROUND AND OBJECTIVES: Mucocutaneous bleeding (MCB) is the main expression of inherited disorders of primary hemostasis. However, the relative prevalence of these disorders, their clinical differential diagnosis, and the proportion of patients with MCB of unknown cause (BUC) after an initial comprehensive laboratory testing are unknown. DESIGN AND METHODS: We studied prospectively 280 consecutive patients with MCB and 299 matched controls, using strict inclusion and exclusion criteria. A single physician recorded the clinical data in a bleeding score and estimated the severity of bleeding in clinical categories. Laboratory criteria for the diagnosis of von Willebrand's disease (VWD) and platelet function defects were established from reference values derived from controls. RESULTS: Fifty patients (17.9%) had VWD (type 1VWD=45, type 2=5). Platelet function defects and mild clotting factor deficiencies were found in 65 (23.2%) and 11 (3.9%) patients, respectively. Thirteen (11.5%) patients had combined defects. The remaining 167(59.6%) patients had BUC, with prolonged bleeding time in 18.6% as their only abnormality. All these disorders, including BUC, were clinically undistinguishable. Moreover, no relationship was found between the severity of bleeding and VWF/platelet function variables. INTERPRETATION AND CONCLUSIONS: The diagnostic efficacy of a first laboratory testing in patients with hereditary MCB is 40.4%. Most patients have a disease(s) of high prevalence but unknown pathogenesis. Concurrent bleeding disorders in the same patient are frequent. Our results support the proposal that low plasma VWF levels, but also platelet function defects, should be considered risk factors rather than unequivocal causes of hemorrhages.

Valproate-associated coagulopathies are frequent and variable in children.

PURPOSE: Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. The clinical relevance of coagulopathies, known as side effects of VPA therapy, especially thrombocytopenia, von Willebrand disease, and a decrease of factor XIII, is still unclear. METHODS: In our institute, we noticed a high incidence of clinically relevant coagulation problems related to VPA in eight patients within 1 year only and a further seven children with significant coagulopathy were identified in the context of planned surgery. RESULTS: We provide an overview of these patients and all six VPA-induced coagulopathies. CONCLUSIONS: At this time, it cannot be recommended to control all hemostatic parameters in every patient. Whenever an increased bleeding tendency is observed, or before surgical procedures, a platelet count, thrombelastography, prothrombin time, activated partial thromboplastin time, TT, fibrinogen, von Willebrand factor, and factor XIII should be examined. With 385 VPA-treated patients per year and 15 cases of coagulation disorders in this period, we estimate the incidence of coagulation disorders related to VPA in children to be nearly 4%.

Rare Bleeding Disorder Registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias.

A North American registry for rare bleeding disorders [factor (F)II, factor (F)VII, factor (F)X, factor (F)V, factor (F)XIII, fibrinogen deficiencies and dysfibrinogenemias] was established to gather information about disease prevalence, genotyping frequency, diagnostic events, clinical manifestations, treatment and prophylaxis strategies, as well as disease- and treatment-related complications. Questionnaires were sent to 225 hemophilia treatment centers in the USA and Canada. Among 26% of responding centers, 294 individuals [4.4% of the registered children (200/4583) and 2.4% of adults (94/3809)] were diagnosed with one or more of the rare bleeding disorders (RBDs) included in this survey. The ethnic distribution for each disorder paralleled that of the general US population with the exception of the disproportionately large number of Latinos with FII deficiency. Only 5.4% of affected individuals were genotyped. An abnormal preoperative bleeding screen most often led to diagnosis. The most common coagulopathy was FVII deficiency; however, 40% of homozygous patients were asymptomatic. FX and FXIII deficiencies caused the most severe bleeding manifestations. Among all RBDs, the most common sites of bleeding were skin and mucus membranes. Multiple products were used to treat hemorrhage; however, half of the bleeding episodes required no therapy. The majority of patients suffered no long-term complications from hemorrhage. Treatment-related complications included viral seroconversion, anemia, allergic reactions and venous access device-related events. This registry provides the most comprehensive information to date about North American individuals with RBDs and could serve as an important resource for both basic scientist and clinician.

Clinical and laboratory management of the prothrombin G20210A mutation.

OBJECTIVE: To make recommendations regarding the appropriate evaluation for the prothrombin G20210A mutation, as reflected by published evidence and the consensus opinion of recognized experts in the field. DAT SOURCES: Review of the medical literature, primarily since 1996. DATA EXTRACTION AND SYNTHESIS: After an initial assessment of the literature, key points defining the condition, and review of the clinical study design, a draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference on Diagnostic Issues in Thrombophilia before the meeting. Each of the key points and associated recommendations were then presented for discussion at the conference. Recommendations were accepted if a consensus of 70% of experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS: Consensus was reached on several recommendations concerning the criteria for testing for the prothrombin G20210A mutation and for the method of testing. First, a major point of consensus was that the prothrombin G20210A mutation is a significant risk factor for venous thromboembolism (VTE) and that testing should be considered in the initial evaluation of suspected inherited thrombophilia. Second, although several analytic methods are commonly used for genetic testing for the prothrombin mutation, all are generally robust and reliable. The recommendations for testing for the prothrombin mutation parallel those for the factor V Leiden mutation and include patients with a history of recurrent VTE, a first episode of VTE before the age of 50 years, a history of an unprovoked VTE at any age, thromboses in unusual anatomic sites, or an affected first-degree relative with VTE. A history of VTE related to pregnancy or estrogen use and unexplained pregnancy loss during the second or third trimesters were also considered to be indications for testing. Other scenarios remain controversial or not recommended, including general population screening.

Elevated hemostatic factor levels as potential risk factors for thrombosis.

OBJECTIVES: To review the state of the art relating to elevated hemostatic factor levels as a potential risk factor for thrombosis, as reflected by the medical literature and the consensus opinion of recognized experts in the field, and to make recommendations for the use of specific measurements of hemostatic factor levels in the assessment of thrombotic risk in individual patients. DATA SOURCES: Review of the medical literature, primarily from the last 10 years. DATA EXTRACTION AND SYNTHESIS: After an initial assessment of the literature, key points were identified. Experts were assigned to do an in-depth review of the literature and to prepare a summary of their findings and recommendations. A draft manuscript was prepared and circulated to every participant in the College of American Pathologists Conference XXXVI: Diagnostic Issues in Thrombophilia prior to the conference. Each of the key points and associated recommendations was then presented for discussion at the conference. Recommendations were accepted if a consensus of the 27 experts attending the conference was reached. The results of the discussion were used to revise the manuscript into its final form. CONCLUSIONS: Consensus was reached on 8 recommendations concerning the use of hemostatic factor levels in the assessment of thrombotic risk in individual patients. Detailed discussion of the rationale for each of these recommendations is presented in the article. This is an evolving area of research. While routine use of factor level measurements is not recommended, improvements in assay methodology and further clinical studies may change these recommendations in the future.